Our goal is to develop new drug or peptide therapies for chronic GVHD (cGVHD). We developed a new cGVHD model of multi-organ system injury and advanced the field by making the important observation that IgG deposition in tissues causes cGVHD. Germinal centers (GCs) are sites where B cells produce plasma cells (PCs) that secrete immunoglobulin (Ig). Our central hypothesis is that cGVHD results from a vigorous GC reaction, PC secretion of Ig with deposition in cGVHD organs causing collagen fibrosis, and these processes are treatable using clinically available drugs or as synthesized by Dr. Jay Bradner. These include inhibitors of Bruton's tyrosine kinase (BTK), B cell lymphoma-6 (BCL6), and inositol tetrakisphosphatase 3' kinase (ITPKb). Epigenetic modifiers, including a first-in-class bromodomain inhibitor drug, will be used to optimize BCL6 inhibitor efficacy. Given the importance of TFH IL-21 in cGVHD therapy, we selected a Rho-associated kinase 2 (ROCK2) inhibitor that blocks IL-21 production. The ubiquitin-proteasome system regulates cytokine production and antigen-processing; PCs are dependent upon proteasome function for survival. Bortezomib inhibits the constitutive proteasome and the immunoproteasome. Our preclinical data indicate that nano-encapsulation improves efficacy and will be further explored. Since constitutive proteasomes degrade and process many antigens, we will use a more selectively target the immunoproteasome, which regulates Ab production. Since cGVHD patients are highly susceptible to viral infections yet benefit from anti- leukemia effects, we will test our top agent for effects on anti-viral and -tumor responses in cGVHD mice as a prelude to clinical trials in cGVHD. To curtail fibrogenic mechanisms, we will target monocytes/macrophage survival, inhibit the production of or response to TGFb. We will build upon our striking data that lung fibrosis and collagen type V (col V) deposition can be prevented by in vivo tolerization with a collagen V peptide. Aim 1: GC B cells & PCs are critical targets for ameliorating cGVHD. We will test the hypotheses that key transcription factors and signaling pathways critical for GC and PC generation will prevent cGVHD (1A). We will test nanoparticle delivery and selectively targeting the immunoproteasome in PCs (1B). Aim 2. TGFb release by donor macrophages results in collagen deposition and fibrosis. We will test the hypothesis that a FcR+ cells are activated by IgG to release TGFb that induces col V in fibrotic organs (2A). We will test the hypothesis that col V peptide-induced tolerization can suppress lung fibrosis via TGFb effects and col V responses (2B). cGVHD therapeutic agents will permit effective anti-viral and GVL responses. We hypothesize that GVL (3A) and anti-viral (3B) responses will be retained with preferred agents from aims 1,2. Strengths include importance of new drug therapies for cGVHD, unique mice and reagents for clinical trials, a strong medicinal chemistry consortium, and strong investigators with expertise in B cell biology and fibrosis.